Phenyl piperazine compounds, pharmaceutical composition including the same and use thereof

ABSTRACT

The present invention relates to novel piperazine derivatives or pharmaceutically acceptable salts thereof, a process for preparing the same, and in particular, a high binding for Serotonin 1A(5-hydroxytryptamine; 5-HT1A) receptor, a pharmaceutical composition for treatment and/or prevention of depression and anxiety including an effective amount of the piperazine compound, and a method of treating depression, anxiety and other conditions related to 5-HT1A receptor in a mammal.

CROSS-REFERENCE

The present application is a continuation-in-part of co-pending U.S.patent application Ser. No. 12/128,999, filed May 29, 2008 of which theentire disclosure is specifically incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to novel piperazine derivatives orpharmaceutically acceptable salts thereof, a process for preparing thesame, and in particular, a high binding for Serotonin1A(5-hydroxytryptamine; 5-HT1A) receptor, a pharmaceutical compositionfor treatment and/or prevention of depression and anxiety including aneffective amount of the piperazine compound, and a method of treatingdepression, anxiety and other conditions related to 5-HT1A receptor in amammal.

BACKGROUND OF THE INVENTION

Depression affects approximately 14 million people in the United Statesand 340 million people worldwide, making it one of the leading causes ofdisability [Kessler R C. Et al., JAMA, 2003, 289, 3095-3105]. Depressionis also associated with high rates of relapse, recurrence, disability,and death [Hirschfield R M., et al., JAMA, 1997, 277, 333-340; Keller MB., J. Psychopharmacol. 1996, 10(suppl 1); 41-44].

The role of serotonin in the treatment of depressive and anxietydisorders is underscored by the therapeutic action of selective 5-HTreuptake inhibitors acting to enhance the degree of activation ofvarious 5-HT receptor subtypes [Blier P. and Ward M., Biol. Psychiatry,2003, 53, 193-203]. Selective serotonin reuptake inhibitors (SSRIs) havehad significant success in treating depression and related disorders andhave become among the most prescribed drugs since 1980s. But, the use ofSSRIs leads to the indiscriminate activation of all serotonin receptorsand it can be understood as undesirable actions of serotonin inundesirable pathways at undesirable receptor subtypes [Stahl S M., 2008,Essential Psychopharmacology (3^(rd) ed.), 531]. Although there arevarious treatment options for depressive and anxiety disorders, a needstill exists for new drugs with improved tolerability and adequateefficacy.

In contrast to the SSRIs, the 5-HT1A agonist or partial agonist actsdirectly on postsynaptic serotonin receptors to increase serotonergicneurotransmission. And, the 5-HT1A partial agonists, Buspirone andGepirone [Robinson D S., et al., J. Clin. Psychopharmacol., 1990, 10(3),67S-76S; Bielski R J., J. Clin. Psychiatry, 2008, 69(4), 571-577], and5-HT1A agonist, Flexinoxan [Grof P., International Clin.Psychopharmacology, 1993, 8(3), 167-172], have shown efficacy inclinical trials for the treatment of depression. Moreover, because oftheir unique pharmacological profile, 5-HT1A agonists possess theoreticadvantages in the treatment of major depression relative to otherclasses of antidepressants. In particular, these drugs are not expectedto produce weight gain, sedation, or sexual dysfunctions, which areoften encountered with some of the antidepressants introduced in thelast 10 years [Blier P. and Ward M., Biol. Psychiatry, 2003, 53,193-203].

Many reports have disclosed that phenyl piperazine compounds areeffectively used for controlling depression and anxiety.

For example, U.S. Pat. No. 5,578,596 discloses that the2-alkoxy-5,6,7,8-tetrahydroquinoxaline derivatives have a strongaffinity for serotonin 1A receptor and are useful for preventing andtreating serotonergic neuron-related disease.

These compounds are found to be very effective as therapeuticalmedicines for managing depression and anxiety.

Active research and development efforts have continued to be directed tothe application of phenyl piperazine compounds for the treatment ofdepression and anxiety.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a piperazine compound representedby Formula (I):

or pharmaceutically acceptable salts thereof, wherein

n is an integer from 2 to 6;

R1 and R2 are the same or different and are independently selected fromthe group consisting of hydrogen, a hydroxyl group, a halogen, nitrogendioxide, a straight or branched chain alkyl group with 1 to 4 carbonatoms, and a straight or branched chain alkoxy group with 1 to 4 carbonatoms;

R3 is a C1-C2 alkylene; and

R4 is selected from the group consisting of:

-   -   (a) a C2-C6 dialkylamine,    -   (b) a 5 to 9-membered aromatic amine wherein the ring is        independently substituted with at least of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (c) a 5 to 9-membered heteroaromatic amine comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (d) a 5 to 9-membered heterocyclic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen, and    -   (e) a 5 to 9-membered heteroaromatic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen; and

R4 is connected to R3 group through a nitrogen atom therein.

In another aspect, the invention provides a pharmaceutical compositioncomprising:

(A) an effective amount of a piperazine compound represented by Formula(I):

or pharmaceutically acceptable salts thereof, wherein

n is an integer from 2 to 6;

R1 and R2 are the same or different and are independently selected fromthe group consisting of hydrogen, a hydroxyl group, a halogen, nitrogendioxide, a straight or branched chain alkyl group with 1 to 4 carbonatoms, and a straight or branched chain alkoxy group with 1 to 4 carbonatoms;

R3 is a C1-C2 alkylene; and

R4 is selected from the group consisting of:

-   -   (a) a C2-C6 dialkylamine,    -   (b) a 5 to 9-membered aromatic amine wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (c) a 5 to 9-membered heteroaromatic amine comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (d) a 5 to 9-membered heterocyclic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen, and    -   (e) a 5 to 9-membered heteroaromatic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen; and

R4 is connected to R3 group through a nitrogen atom therein; and

(B) a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the invention provides a method for treating atleast one of depression and anxiety in a mammal comprising administeringto a mammal in need thereof an effective amount of a piperazine compoundrepresented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein

n is an integer from 2 to 6;

R1 and R2 are the same or different and are independently selected fromthe group consisting of hydrogen, a hydroxyl group, a halogen, nitrogendioxide, a straight or branched chain alkyl group with 1 to 4 carbonatoms, and a straight or branched chain alkoxy group with 1 to 4 carbonatoms;

R3 is a C1-C2 alkylene; and

R4 is selected from the group consisting of:

-   -   (a) a C2-C6 dialkylamine,    -   (b) a 5 to 9-membered aromatic amine wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (c) a 5 to 9-membered heteroaromatic amine comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (d) a 5 to 9-membered heterocyclic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen, and    -   (e) a 5 to 9-membered heteroaromatic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen; and

R4 is connected to R3 group through a nitrogen atom therein.

DETAILED DESCRIPTION OF THE INVENTION

Before any embodiments of the invention are explained in detail, it isto be understood that the invention is not limited in its application tothe details of construction and the arrangement of components set forthin the following description. The invention is capable of otherembodiments and of being practiced or of being carried out in variousways. Also, it is to be understood that the phraseology and terminologyused herein is for the purpose of description and should not be regardedas limiting. The use of “including,” “comprising,” or “having” andvariations thereof herein is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

It also is understood that any numerical range recited herein includesall values from the lower value to the upper value. For example, if aconcentration range is stated as 1% to 50%, it is intended that valuessuch as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expresslyenumerated in this specification. These are only examples of what isspecifically intended, and all possible combinations of numerical valuesbetween and including the lowest value and the highest value enumeratedare to be considered to be expressly stated in this application.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof as well as mixtures in different proportions of theseparate enantiomers, where such isomers and enantiomers exist, as wellas pharmaceutically acceptable salts thereof and solvates thereof suchas, for instance, hydrates. Isomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallization. Theenantiomers may be isolated by separation of racemates for example byfractional crystallization, resolution, or HPLC. The diastereomers maybe isolated by separation of isomer mixtures for instance by fractionalcrystallization, HPLC, or flash chromatography.

A “heteroaromatic ring” or a “heterocylic ring” means a ring containingat least one heteroatom. A “heteroatom” means an atom other than carbonin the ring of a heterocylic group or a heteroaromatic group.Heteroatoms may be at least one of oxygen, sulfur, and nitrogen atoms.Groups containing more than one heteroatom may contain differentheteroatoms.

An “effective amount” means any amount that yields a therapeutic effect.

“Pharmaceutically acceptable” means suitable for use in a human or othermammal.

“Excipient” as used herein includes physiologically compatible additivesuseful in preparation of a pharmaceutical composition. Examples ofpharmaceutically acceptable carriers and excipients can for example befound in Remington Pharmaceutical Science, 16^(th) Ed.

“Pharmaceutically acceptable carrier” means a carrier that is useful forthe preparation of a pharmaceutical composition that is generallycompatible with the other ingredients of the composition, notdeleterious to the recipient, and neither biologically nor otherwiseundesirable. “A pharmaceutically acceptable carrier” includes one ormore than one carrier. Embodiments include carriers for parenteral,intravenous, intraperitoneal, intramuscular, sublingual, nasal and oraladministration. “Pharmaceutically acceptable carrier” also includesagents for preparation of aqueous dispersions and sterile powders forinjection or dispersions.

The piperazine compounds of the invention have Chemical Formula (I) orpharmaceutically acceptable salts thereof.

wherein

n is an integer from 2 to 6;

R1 and R2 are the same or different and are independently selected fromthe group consisting of hydrogen, a hydroxyl group, a halogen, nitrogendioxide, a straight or branched chain alkyl group with 1 to 4 carbonatoms, and a straight or branched chain alkoxy group with 1 to 4 carbonatoms;

R3 is a C1-C2 alkylene; and

R4 is selected from the group consisting of:

-   -   (a) a C2-C6 dialkylamine,    -   (b) a 5 to 9-membered aromatic amine wherein the ring is        independently substituted with at least of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (c) a 5 to 9-membered heteroaromatic amine comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen,    -   (d) a 5 to 9-membered heterocyclic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen, and    -   (e) a 5 to 9-membered heteroaromatic ring comprising at least a        nitrogen atom as a ring constituent wherein the ring is        independently substituted with at least one of hydrogen, a C1-C6        aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group        and a halogen; and

R4 is connected to R3 group through a nitrogen atom therein.

In one embodiment, R1 and R2 are independently selected from the groupconsisting of hydrogen, a hydroxyl group, a halogen, nitrogen dioxide, astraight or branched chain alkyl group with 1 to 4 carbon atoms, and astraight or branched chain alkoxy group with 1 to 4 carbon atoms. Forexample, the halogen may be F, Cl, Br, or I. The alky group may bemethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, andt-butyl, and particularly may be methyl, ethyl, propyl, isopropyl, andtertiary butyl. Unless otherwise stated or indicated, the term “alkoxy”denotes a group O-alkyl, wherein alkyl is methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.

Unless otherwise stated or indicated, the term “halogen” shall meanfluorine, chlorine, bromine, or iodine.

Examples of R4 include, without limitation, dimethyl amine,diethylamine, dipropylamine, methylethyl amine, methylpropyl amine,methylbutyl amine, and ethylpropy amine.

When R4 is a 5 to 9-membered aromatic amine or a 5 to 9-memberedheteroaromatic amine, R4 is connected to R3 through a nitrogen atom inan amino group.

R4 may be a 5 to 9-membered aromatic amine wherein the ring isindependently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen. In one embodiment, examples of a 5 to 9-membered aromatic aminein R4 is a 5 or 6-membered aromatic amine substituted with at least oneof hydrogen, a C1-C6 alkyl, and a halogen, and particularly, a6-membered aromatic amine substituted with hydrogen, such as aniline.

R4 may be a 5 to 9-membered heteroaromatic amine containing at least anitrogen atom where the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group, and a halogen. In one embodiment, examples of a 5 to9-membered heteroaromatic amine include a 5 or 6-membered heteroaromaticamine substituted with at least one of a C1-C6 alkyl and a halogen,wherein the heteroaromatic amine comprises at least two heteroatoms asring constituents where a first heteroatom is N and a second heteroatomis independently selected from the group consisting of N, O, and S.

The 5-membered heteroaromatic amine may have a structure (II) selectedfrom the group consisting of:

When R4 is a 5 to 9-membered heterocyclic ring or a 5 to 9-memberedheteroaromatic ring, R4 may be connected to R3 through a nitrogen atomcontained in the ring as a heteroatom of the 5 to 9-membered heterocylicring or heteroaromatic ring.

R4 may be a 5 to 9-membered heterocyclic ring containing at least anitrogen atom where the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group, and a halogen. Examples of a 5 to 9-memberedheterocylic ring include, without limitation, a 5 or 6-memberedheterocylic ring having a structure (III) selected from the groupconsisting of:

R4 may be a 5 to 9-membered heteroaromatic ring containing at least anitrogen atom where the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group, and a halogen. Examples of a heteroaromatic ringinclude, without limitation, an azole compound such as diazole,triazole, tetraazol, benzotriazole, imidazole, pyrazole, benzimidazloeor indazole. The azole ring may be independently substituted with atleast one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclicalkyl, a C6-C10 aryl group, and a halogen. The azole compound may have astructure (IV) selected from the group consisting of:

Examples of compounds having Chemical Formula (I) include, withoutlimitation,1-[4-(4-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-[4-(3-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine-hydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzoimidazole,1-(2-Methoxy-phenyl)-4-{4-[4-(2-methyl-imidazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-indazole,1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzotriazole,1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-aminedi-hydrochloride,1-(2-methoxy-phenyl)-4-[4-(4-piperidin-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-phenyl-amine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-thiazol-2-yl-amine,1-(2-chloro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,4-(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,1-{4-[4-(4,5-dichloro-imidazol-1-ylmethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine,1-(2-chloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,4-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,(4-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,1-(3-fluoro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2,3-dichloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,(4-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,4-(4-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-[1,3,4]thiadiazol-2-yl-amine,1-(2,3-dichloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine,1-{4-[4-(2-imidazol-1-yl-ethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-1-yl)-ethyl]-phenoxy}-butyl)-piperazine,1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-2-yl)-ethyl]-phenoxy}-butyl)-piperazine,2-{4-[4-(4-[1,2,3]-triazol-1-ylmethyl-phenoxy)-butyl]-piperazin-1-yl}-benzonitrile,and1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

A “pharmaceutically acceptable salt”, where such salts are possible,includes both pharmaceutically acceptable acid and base addition salts.A suitable pharmaceutically acceptable salt of a compound of Formula Iis, for example, an acid-addition salt of a compound of Formula I thatis sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example, a salt of acompound of Formula I that is sufficiently acidic, for example an alkalior alkaline earth metal salt such as a sodium, calcium, or magnesiumsalt, or an ammonium salt, or a salt with an organic base such asmethylamine, dimethylamine, trimethylamine, piperidine, morpholine, ortris-(2-hydroxyethyl)amine.

A method for preparing the above piperazine derivative, represented bychemical Formula (I) will be described below in detail.

First, phenols of Formula (VI) as starting material are reacted withdihalide alkanes represented by Formula (V) to synthesize halogenizedcompounds represented by Formula (VII):

wherein n is the same as defined above and X is a halogen such as,without limitation, chloride and bromide.

The halogenized compound represented by Formula (VII) is reacted withphenyl piperazines of Formula (VIII) to obtain the compounds havinghydroxy group represented by the Formula (IX):

wherein R1, R2, n and R3 are the same as defined above.

This procedure is summarized as set forth in Reaction Scheme (I) below.

Details of the reaction conditions described in Reaction Scheme I may beas follows. For the conversion of the phenols (VI) to the halogenizedcompound (VII), the concentration of the phenols (VI) may be about 0.005to about 0.1 moles, with a dihalide alkane (V) ranging from about 2.0 toabout 3.0 equivalents and an organic or inorganic base from about 3.0 toabout 4.0 equivalents. This reaction may be refluxed. The resultingproduct may be purified by column chromatography. For the conversion ofthe halogenized compounds (VII) to the compound having hydroxy group(IX), a mixture of (VII) and substituted phenylpiperazine (VIII) may berefluxed in about 30 ml of acetonitrile for about 6 h. For this couplingreaction, an ethereal solvent such as diethyl ether and tetrahydrofuran,a halogenated hydrocarbon solvent such as dichloromethane andchloroform, or a mixture thereof may be used.

Then, the hydroxy compounds having hydroxy group represented by Formula(IX) are reacted with thionyl chloride and then with dialkylamines,aromatic amine, heteroaromatic amine, heterocyclic ring, orheteroaromatic ring groups to produce the phenyl piperazine compoundsrepresented by Formula (I):

wherein,

R1, R2, R3, R4, and n are as previously defined.

The pharmaceutically acceptable salts thereof represented by Formula(XI) as below can be obtained by treating a phenyl piperazine compoundof Formula (I) with an anhydrous acid in a solution without furtherpurification.

This procedure is summarized as set forth in Reaction Scheme (II) below.

Details of the reaction conditions described in Reaction Scheme II areas follows. For the conversion of the compounds having hydroxy group(IX) to the compound (X), the concentration of the compounds havinghydroxy group (IX) may be about 0.005 to about 0.1 moles with thionylchloride ranging from about 1.0 to about 1.5 equivalents. This reactionmay be carried out at a temperature of about 0° C. The resulting productmay be purified by column chromatography. The resulting compound (X) maybe treated with about 2.0 to about 3.0 equivalents of dialkylamines,aromatic amine, heteroaromatic amine, heterocyclic ring, orheteroaromatic ring at a reflux to give the compound of the GeneralFormula (I). For this coupling reaction, tetrahydrofuran, acetonitrile,a halogenated hydrocarbon solvent such as dichloromethane andchloroform, or a mixture thereof may be used.

In Reaction Scheme II, HA represents an acid that is capable of forminga pharmacologically useful salt with the basic nitrogen atom. Specificexamples of the anhydrous acid used for the preparation of the compound(XI) include, without limitation, hydrochloric acid, sulfuric acid,phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid,salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid,tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid,aspartic acid, benzene sulfonic acid, methane sulfonic acid, ethanesulfonic acid, hydroxymethane sulfonic acid, hydroxyethane sulfonicacid, and the like. For additional acids, one can refer to“Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66(1): 1-19. Thispreparation may be executed in a reaction media that can be exemplifiedby an ethereal solvent such as tetrahydrofuran, an alcoholic solventsuch as methanol, an ester solvent such as ethyl acetate, a halogenatedhydrocarbon solvent, and mixtures thereof. In one embodiment, anethereal solvent is recommended as an addition solution, including ethylether, propyl ether, isopropyl ether, butyl ether, and isobutyl ether.The concentration of the compound (I) may be in the order of about 0.01to about 5 moles.

In another embodiment of the present invention, the present inventionprovides a pharmaceutical composition including an effective amount ofphenyl piperazine compounds represented by Formula (I) for treating atleast one of depression and anxiety.

In a further embodiment of the present invention, the present inventionprovides a method of treating at least one of depression and anxiety ina mammal comprising administering to a mammal in need thereof aneffective amount of the piperazine compounds represented by StructuralFormula (I), alone or in combination with a pharmaceutically acceptablecarrier or excipient.

The activity of the compounds of the present invention was examinedthrough the Mouse Tail Suspension and Marble Burying Test.

In therapeutic use as agents for depression and anxiety the compounds ofthe present invention are used, alone or in combination with apharmaceutically acceptable carrier or excipient. Standardpharmaceutical formulation techniques may be used, such as thosedisclosed in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa. (1990). The compounds of the present invention maybe administered orally or parentally, neat or in combination withconventional pharmaceutical carriers. “Carrier” means one or morecompatible substances that are suitable for administration to a mammal.Carrier includes solid or liquid fillers, diluents, hydrotopes,surface-active agents, and encapsulating substances. “Compatible” meansthat the components of the composition are capable of being commingledwith the piperazine compounds represented by Structural Formula (I), andwith each other, in a manner such that there is no interaction whichwould substantially reduce the efficacy of the composition underordinary use situations. Carriers must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the mammal being treated. The carrier can be inert, or it can possesspharmaceutical benefits, cosmetic benefits, or both.

The choice of carrier depends on the route by which the piperazinecompounds represented by Structural Formula (I) will be administered andthe form of the composition. The composition may be in a variety offorms, suitable, for example, for systemic administration (e.g., oral,rectal, nasal, sublingual, buccal, or parenteral).

The exact amounts of each component in the pharmaceutical compositiondepend on various factors. The amount of the piperazine compoundrepresented by Structural Formula (I) depends on the binding affinity(IC₅₀) of the medicament selected. The amount of the carrier employed inconjunction with the medicament is sufficient to provide a practicalquantity of material for administration per unit dose of the compound.Techniques and compositions for making dosage forms useful in themethods of this invention are described in the following references:Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

Applicable solid carriers can include, without limitation, one or moresubstances which may also act as flavoring agents, lubricants,solubilizers, suspending agents, fillers, glidants, compression aids,binders, tablet-disintegrating agents, or encapsulating materials. Inpowders, the carrier may be a finely divided solid that may be inadmixture with the finely divided active ingredient. In tablets, theactive ingredient may be mixed with a carrier having suitablecompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets may contain up to about99% of the active ingredient.

Suitable solid carriers include, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins. Liquidcarriers may be used in preparing solutions, suspensions, emulsions,syrups, and elixirs.

The active ingredient of this invention may be dissolved or suspended ina pharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both, or pharmaceutically acceptable oils or fats.The liquid carrier may contain other suitable pharmaceutical additivessuch as solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g., cellulose derivativessuch as, without limitation, a sodium carboxymethyl cellulose solution),alcohols (including, without limitation, monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., without limitation, fractionated coconut oil and arachis oil).

For parenteral administration the carrier can also be an oily ester suchas ethyl oleate and isopropyl myristate. Sterile liquid carriers areused in sterile liquid form compositions for parenteral administration.Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal, or subcutaneous injection. Sterile solutions can alsobe administered intravenously.

Oral administration may be either in liquid or solid composition form.In one embodiment, the pharmaceutical compositions containing thepresent compounds are in unit dosage form, e.g., as tablets or capsules.In such form, the composition may be sub-divided in unit dosagescontaining appropriate quantities of the active ingredients. The unitdosage forms can be packaged compositions, for example, packagedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. Alternatively, the unit dosage form can be, for example, acapsule or tablet itself, or it can be the appropriate number of anysuch compositions in package form. The therapeutically effective dosageto be used may be varied or adjusted by the physician and generallyranges from about 0.5 mg to about 750 mg, according to the specificcondition(s) being treated and the size, age, and response pattern ofthe patient.

An effective amount of a compound according to the present inventionwill vary with the particular condition being treated, the age andphysical condition of the patient being treated, the severity of thecondition, the duration of treatment, the nature of concurrent therapy,the route of administration, the particular pharmaceutically-acceptablecarrier utilized, and like factors within the knowledge and expertise ofthe attending physician. The compounds of the present invention may beadministered to patients at a dosage of from about 0.7 to about 7000 mgper day, particularly about 1.0 to about 1000 mg. For example, for anormal human adult with a body weight of approximately 70 kg, theadministration amount is translated into a daily dose of about 0.01 toabout 100 mg per kg of body weight. The specific dosage employed,however, may vary depending upon the requirements of the patient, theseverity of the patient's condition, and the activity of the compound.The determination of optimum dosages for a particular situation may beclinically done and is within the skill of the art. While these dosagesare based upon a daily administration rate, the compounds of the presentinvention may also be administered at other intervals, such as twice perday, twice weekly, once weekly, or once a month. One of ordinary skillin the art would be able to calculate suitable effective amounts forother intervals of administration.

The exact amounts of each component in the pharmaceutical compositiondepend on various factors. The amount of the piperazine compound addedto the pharmaceutical composition is dependent on the IC50 of thecompound, typically expressed in nanomolar (nM) units. For example, ifthe IC50 of the medicament is 1 nM, the amount of the piperazinecompound will be from about 0.001 to about 0.3%. If the IC50 of themedicament is 10 mM, the amount of the piperazine compound will be fromabout 0.01 to about 1%. If the IC50 of the medicament is 100 nM, theamount of the piperazine compound will be from about 0.1 to about 10%.If the IC50 of the medicament is 1000 nM, the amount of the piperazinecompound will be 1 to 100%, preferably 5% to 50%. If the amount of thepiperazine compound is outside the ranges specified above (i.e., lower),efficacy of the treatment may be reduced. One skilled in the artunderstands how to calculate and understand an IC50. The remainder ofthe composition, up to 100%, may be a pharmaceutically acceptablecarrier or excipient.

A better understanding of the present invention may be obtained in lightof the following examples to illustrate, but are not to be construed tolimit, the present invention.

Example 11-[4-(4-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine

A mixture of 4-hydroxybenzaldehyde (5 mmol), 1-bromo-4-chlorobutane (5mmol), and potassium carbonate (15 mmol) was refluxed in 100 ml ofacetone for 6 h. This solution was then concentrated on a rotaryevaporator and diluted with ethyl acetate. This mixture was then washedwith brine, and the resulting organic layer was dried and purified bycolumn chromatography. This was dissolved in methanol (50 ml) and wasadded with sodium borohydride (10 mmol) at 25° C. This mixture wasstirred at 25° C. for 2 h. This solution was then concentrated in arotary evaporator and diluted with methylene chloride, then washed withbrine, and the resulting organic layer was dried and concentrated invacuo. The crude product was dissolved in isopropanol (50 ml) and wasadded with 1-(2-methoxyphenyl)-piperazine (5 mmol), sodium carbonate (15mmol), and potassium iodide (5 mmol) at 25° C., and the reaction mixturewas refluxed for 12 h. This solution was then concentrated on a rotaryevaporator and diluted with methylene chloride, then washed with brine,and the resulting organic layer was dried and purified by columnchromatography. This product was dissolved in CHCl3 (30 ml) and wasadded with pyridine and thionyl chloride (5 mmol) at 0° C., then stirredat room temperature for 16 h, and water was added to terminate thereaction. The organic layer was extracted 3 times with dichloromethane,dried, and concentrated in vacuo. The residue was purified by columnchromatography. This was dissolved in acetonitrile (30 ml) and was addedwith imidazole (6 mmol), potassium carbonate (15 mmol), and potassiumiodide (5 mmol) at 25° C., and the reaction mixture was refluxed for 12h. This solution was then concentrated in a rotary evaporator anddiluted with methylene chloride, then washed with brine, and theresulting organic layer was dried and purified by column chromatography.The resulting1-[4-(4-imidazole-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazinewas dissolved in dichloromethane and the solution was treated with asolution of HCl in ethyl ether. The resulting precipitate was filteredto give1-[4-(4-imidazole-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazinehydrochloride.

¹H-NMR (CDCl₃, 200 MHz) δ 11.1 (br, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.2(m, 2H), 6.9 (m, 7H), 5.0 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m,4H), 2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 21-(2-methoxy-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using 1H-1,2,4-triazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-[1,2,4]triazole-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.1 (s, 1H), 8.0 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.2 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H),2.5 (t, 2H), 1.8 (m, 4H)

Example 31-(2-methoxy-phenyl)-4-[4-(4-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using 1H-tetrazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.6 (s, 1H), 7.2 (m, 2H), 7.0 (m, 6H), 5.6 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H) 3.2 (m, 4H), 2.9 (m, 4H), 2.7 (t, 2H), 1.9(m, 4H)

Example 41-(2-methoxy-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using 1H-tetrazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.6 (s, 1H), 7.2 (m, 2H), 7.0 (m, 6H), 5.8 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H) 3.2 (m, 4H), 2.9 (m, 4H), 2.7 (t, 2H), 1.9(m, 4H)

Example 51-[4-(3-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine-hydrochloride

A mixture of 3-hydroxybenzaldehyde (5 mmol), 1-bromo-4-chlorobutane (5mmol), and potassium carbonate (15 mmol) was refluxed in 100 ml ofacetone for 6 h. This solution was then concentrated in a rotaryevaporator and diluted with ethyl acetate, then washed with brine, andthe resulting organic layer was dried and purified by columnchromatography. This was dissolved in methanol (50 ml) and was addedwith sodium borohydride (10 mmol) at 25° C., and was stirred at 25° C.for 2 h. This solution was then concentrated in a rotary evaporator anddiluted with methylene chloride, then washed with brine, and theresulting organic layer was dried and concentrated in vacuo. The crudeproduct was dissolved in isopropanol (50 ml) and was added with1-(2-methoxyphenyl)-piperazine (5 mmol), sodium carbonate (15 mmol), andpotassium iodide (5 mmol) at 25° C., and the reaction mixture wasrefluxed for 12 h. This solution was then concentrated in a rotaryevaporator and diluted with methylene chloride, then washed with brine,and the resulting organic layer was dried and purified by columnchromatography. This product was dissolved in CHCl₃ (30 ml) and wasadded with pyridine and thionyl chloride (5 mmol) at 0° C., and then theresulting reaction mixture was stirred at room temperature for 16 h, andwater was added to terminate the reaction. The organic layer wasextracted 3 times with dichloromethane, then dried and concentrated invacuo, and the residue was purified by column chromatography. This wasdissolved in acetonitrile (30 ml) and was added with imidazole (6 mmol),potassium carbonate (15 mmol), and potassium iodide (5 mmol) at 25° C.,and the reaction mixture was refluxed for 12 h. This solution was thenconcentrated in a rotary evaporator and diluted with methylene chloride,then washed with brine, and the resulting organic layer was dried andpurified by column chromatography. The resulting1-[4-(3-imidazole-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazinewas dissolved in dichloromethane and the solution was treated with asolution of HCl in ethyl ether. The resulting precipitate was filteredto give1-[4-(3-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazinehydrochloride.

¹H-NMR (DMSO, 200 MHz) δ 11.6 (br, 1H), 9.5 (s, 1H), 7.8 (s, 1H), 7.6(s, 1H), 7.2 (m, 2H), 7.0 (m, 6H), 5.4 (s, 2H), 4.0 (t, 2H), 3.8 (s,3H), 3.6-3.2 (m, 10H), 2.0 (m, 2H), 1.8 (m, 2H)

Example 61-(2-methoxy-phenyl)-4-[4-(3-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride

The procedure given in Example 5 was followed using 1H-1,2,4-triazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(3-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (DMSO, 200 MHz) δ 11.6 (br, 1H), 9.5 (s, 1H), 8.5 (s, 1H), 7.2(m, 2H), 7.0 (m, 6H), 5.4 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6-3.2 (m,10H), 2.0 (m, 2H), 1.8 (m, 2H)

Example 71-(2-methoxy-phenyl)-4-[4-(3-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride

The procedure given in Example 5 was followed using 1H-tetrazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (DMSO, 200 MHz) δ 10.8 (br, 1H), 9.6 (s, 1H), 7.2 (m, 2H), 7.0(m, 6H), 5.4 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (m, 4H), 3.2 (m,6H), 2.0 (m, 2H), 1.8 (m, 2H)

Example 81-(2-methoxy-phenyl)-4-[4-(3-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride

The procedure given in Example 5 was followed using 1H-tetrazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (DMSO, 200 MHz) δ 10.8 (br, 1H), 9.0 (s, 1H), 7.2 (m, 2H), 7.0(m, 6H), 5.9 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (m, 4H), 3.2 (m,6H), 2.0 (m, 2H), 1.8 (m, 2H)

Example 91-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzoimidazole

The procedure given in Example 1 was followed using 1H-benzoimidazole asreactants, instead of imidazole, to give1-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzoimidazole.

¹H-NMR (CDCl₃, 200 MHz) δ 8.0 (s, 1H), 7.8 (m, 1H), 7.3 (m, 3H), 7.2 (m,2H), 7.0 (m, 6H), 5.3 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H),2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 101-(2-Methoxy-phenyl)-4-{4-[4-(2-methyl-imidazol-1-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using 2-methyl-imidazoleas reactants, instead of imidazole, to give1-(2-Methoxy-phenyl)-4-{4-[4-(2-methyl-imidazol-1-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.1˜6.8 (m, 10H), 5.0 (s, 2H), 4.0 (t, 2H),3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.2 (s, 3H), 1.8 (m,4H)

Example 111-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using 1H-1,2,3-triazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazole-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (s, 2H), 7.2 (m, 2H), 6.9 (m, 6H), 5.6 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 121-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using 1H-1,2,3-triazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazole-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.7 (s, 1H), 7.4 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.5 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H),2.5 (t, 2H), 1.8 (m, 4H)

Example 131-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-indazole

The procedure given in Example 1 was followed using 1H-Indazole asreactants, instead of imidazole, to give1-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-indazole.

¹H-NMR (CDCl₃, 200 MHz) δ 8.1 (s, 1H), 7.7 (m, 1H), 7.3 (m, 3H), 7.2 (m,2H), 7.0 (m, 6H), 5.3 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H),2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 141-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzotriazole

The procedure given in Example 1 was followed using benzotriazole asreactants, instead of imidazole, to give1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzotriazole.

¹H-NMR (CDCl₃, 200 MHz) δ 8.1 (m, 1H), 7.4˜7.2 (m, 5H), 7.0˜6.8 (m, 6H),5.8 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t,2H), 1.8 (m, 4H)

Example 151-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using5-phenyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.2 (m, 2H), 7.6 (m, 5H), 7.2˜7.0 (m, 6H), 5.8(s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t,2H), 1.8 (m, 4H)

Example 161-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using5-phenyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (m, 4H), 7.2 (m, 3H), 6.9 (m, 6H), 5.6 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 171-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using5-methyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.4 (m, 2H), 7.0 (m, 6H), 5.6 (s, 2H), 4.0 (t,2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.5 (s, 3H),1.8 (m, 4H)

Example 181-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using5-methyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 7.0 (m, 6H), 5.4 (s, 2H), 4.0 (t,2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.5 (s, 3H),1.8 (m, 4H)

Example 19(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-aminedihydrochloride

The procedure given in Example 1 was followed using dimethyl amine asreactants, instead of imidazole, to give(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-aminedihydrochloride.

¹H-NMR (DMSO, 200 MHz) δ 11.3 (br, 1H), 11.1 (br, 1H), 7.5 (m, 2H), 7.0(m, 6H), 4.2 (m, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (m, 4H), 3.2 (m,6H), 2.6 (m, 6H), 1.8 (m, 4H)

Example 201-(2-methoxy-phenyl)-4-[4-(4-piperidin-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using piperidine asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-piperidin-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 6.9 (m, 6H), 4.0 (t, 2H), 3.8 (s,3H), 3.4 (s, 2H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.4 (m, 4H),1.8 (m, 4H), 1.6 (m, 4H), 1.4 (m, 2H)

Example 21(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-phenyl-amine

The procedure given in Example 1 was followed using aniline asreactants, instead of imidazole, to give(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-phenyl-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 7.0 (m, 6H), 6.8 (m, 5H), 4.3 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (s, 1H), 3.2 (m, 4H), 2.7 (m, 4H),2.5 (t, 2H), 1.8 (m, 4H)

Example 22 (10663)(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-thiazol-2-yl-amine

The procedure given in Example 1 was followed using thiazol-2-ylamine asreactants, instead of imidazole, to give(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-thiazol-2-yl-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.5 (s, 1H), 7.2 (m, 2H), 7.0 (m, 6H), 6.6 (s,1H), 4.3 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (s, 1H), 3.2 (m, 4H),2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 231-(2-chloro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and 1H-1,2,4-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2-chloro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.1 (s, 1H), 8.0 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.2 (s, 2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 241-(2-methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 5 was followed using 1H-1,2,3-triazole asreactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (s, 2H), 7.2 (m, 2H), 6.9 (m, 6H), 5.4 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 251-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 5 was followed using 1H-1,2,3-triazole asreactants, instead of Imidazole, to give1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.7 (s, 1H), 7.4 (s, 1H), 7.2 (m, 2H), 7.0-6.8(m, 6H), 5.5 (s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m,4H), 2.5 (t, 2H), 2.5 (s, 3H), 1.8 (m, 4H)

Example 261-(2-Methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 5 was followed using5-methyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-Methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (s, 2H), 7.2 (m, 2H), 7.0-6.8 (m, 6H), 5.5(s, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t,2H), 2.5 (s, 3H), 1.8 (m, 4H)

Example 271-(2-methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 5 was followed using5-methyl-1H-tetrazole as reactants, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 7.0-6.7 (m, 6H), 5.5 (s, 2H), 4.0(t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.5 (s,3H), 1.8 (m, 4H)

Example 28(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine

The procedure given in Example 5 was followed using dimethyl amine asreactants, instead of imidazole, to give(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.3 (m, 2H), 6.9 (m, 6H), 4.0 (t, 2H), 3.9 (s,3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.6 (s, 6H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 294-(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine

The procedure given in Example 5 was followed using morpholine asreactants, instead of imidazole, to give4-(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine.

¹H-NMR (CDCl₃, 200 MHz) 7.2 (m, 2H), 6.9 (m, 6H), 4.1 (t, 2H), 3.9 (s,3H), 3.7 (m, 4H), 3.5 (s, 2H), 3.2 (m, 4H), 2.8 (m, 4H), 2.6 (t, 2H),2.5 (m, 4H), 1.8 (m, 4H)

Example 301-{4-[4-(4,5-dichloro-imidazol-1-ylmethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine

The procedure given in Example 1 was followed using4,5-dichloro-imidazole as reactants, instead of imidazole, to give1-{4-[4-(4,5-dichloro-imidazol-1-ylmethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.4 (s. 1H), 7.2 (m, 2H), 6.9 (m, 6H), 5.0 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 311-(2-chloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and 1H-tetrazole as reactants, instead of1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2-chloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.5 (m, 1H), 7.4 (m, 4H), 7.0 (m, 2H), 6.8 (m,2H), 5.8 (s, 2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.9 (m, 4H), 2.7 (t, 2H),1.9 (m, 4H)

Example 324-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine

The procedure given in Example 1 was followed using morpholine asreactants, instead of imidazole, to give4-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 6.9 (m, 6H), 4.0 (t, 2H), 3.8 (s,3H), 3.4 (s, 2H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.4 (m, 4H),1.8 (m, 4H), 1.6 (m, 4H)

Example 33(4-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and dimethylamine, instead of1-(2-methoxyphenyl)-piperazine and imidazole, to give(4-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.3˜7.1 (m, 4H), 7.1˜6.8 (m, 4H), 4.2 (t, 2H),3.4 (m, 2H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (m, 2H), 2.4 (s, 6H), 1.8˜1.7(m, 4H)

Example 341-(3-fluoro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(3-fluoro-phenyl)-piperazine and 1H-1,2,4-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(3-fluoro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.9 (s, 1H), 7.7 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.5 (s, 2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.8 (m, 4H), 2.6 (t, 2H),1.8 (m, 4H)

Example 351-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and methylpiperazine, instead of insteadof 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.3˜7.1 (m, 4H), 7.1˜6.8 (m, 4H), 4.3 (t, 2H),3.4 (m, 2H), 3.1 (m, 4H), 2.7 (m, 4H), 2.6 (m, 8H,) 2.5 (m, 2H), 2.3 (s,3H), 1.8˜1.7 (m, 4H)

Example 361-(2,3-dichloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and 1H-tetrazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2,3-dichloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.5 (m, 1H), 7.4-6.8 (m, 7H), 5.8 (s, 2H), 4.0(t, 2H), 3.2 (m, 4H), 2.9 (m, 4H), 2.7 (t, 2H), 1.9 (m, 4H)

Example 371-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and 5-methyl-1H-tetrazole asreactants, instead of 1-(2-methoxyphenyl)-piperazine and imidazole, togive1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 7.0 (m, 5H), 5.4 (s, 2H), 4.0 (t,2H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.6 (s, 3H), 1.8 (m, 4H)

Example 381-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and 5-methyl-1H-tetrazole asreactants, instead of 1-(2-methoxyphenyl)-piperazine and imidazole, togive1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2˜7.0 (m, 7H), 5.6 (s, 2H), 4.0 (t, 2H), 3.1(m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.5 (s, 3H), 1.8 (m, 4H)

Example 39(4-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and dimethyl amine as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give(4-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine.

¹H-NMR (DMSO, 200 MHz) δ 11.3 (br, 1H), 11.1 (br, 1H), 7.5 (m, 2H), 7.0(m, 5H), 4.2 (m, 2H), 4.0 (t, 2H), 3.6 (m, 4H), 3.2 (m, 6H), 2.6 (m,6H), 1.8 (m, 4H)

Example 404-(4-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and morpholine, instead of1-(2-methoxyphenyl)-piperazine and imidazole, to give4-(4-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 6.9 (m, 6H), 4.2 (t, 2H), 3.7 (m,4H), 3.5 (s, 2H), 3.2 (m, 4H), 2.8 (m, 4H), 2.6 (t, 2H), 2.5 (m, 4H),1.8 (m, 4H)

Example 411-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and methylpiperazine, instead of1-(2-methoxyphenyl)-piperazine and imidazole to give1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.3˜6.8 (m, 7H), 4.3 (t, 2H), 3.4 (m, 2H), 3.1(m, 4H), 2.7 (m, 4H), 2.6 (m, 8H,) 2.5 (m, 2H), 2.3 (s, 3H), 1.8˜1.7 (m,4H)

Example 421-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and 1H-1,2,3-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.7 (s, 1H), 7.4 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.5 (s, 2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 43(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-[1,3,4]thiadiazol-2-yl-amine

The procedure given in Example 1 was followed using[1,3,4]Thiadiazol-2-ylamine as reactants, instead of imidazole, to give(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-[1,3,4]thiadiazol-2-yl-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2˜6.8 (m, 9H), 4.3 (s, 2H), 4.0 (t, 2H), 3.8(s, 3H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 441-(2,3-dichloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2,3-dichloro-phenyl)-piperazine and 1H-1,2,3-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2,3-dichloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.7 (s, 1H), 7.4-6.8 (m, 8H), 5.8 (s, 2H), 4.0(t, 2H), 3.2 (m, 4H), 2.9 (m, 4H), 2.7 (t, 2H), 1.9 (m, 4H)

Example 45(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine

The procedure given in Example 1 was followed using5-methyl-isoxazol-3-ylamine as reactants, instead of imidazole, to give(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2˜6.8 (m, 9H), 4.3 (s, 2H), 4.0 (t, 2H), 3.8(s, 3H), 3.6 (s, 1H) 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 2.3 (s, 3H),1.8 (m, 4H)

Example 46(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(3-methyl-isoxazol-5-yl)-amine

The procedure given in Example 1 was followed using3-methyl-isoxazol-5-ylamine as reactants, instead of imidazole, to give(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(3-methyl-isoxazol-5-yl)-amine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2 (m, 2H), 7.0 (m, 6H), 6.8 (s, 1H), 4.3 (s,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.6 (s, 1H), 3.2 (m, 4H), 2.7 (m, 4H),2.5 (t, 2H), 2.3 (s, 3H), 1.8 (m, 4H)

Example 471-{4-[4-(2-imidazol-1-yl-ethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine

A mixture of 4-hydroxyphenetylalcohol (5 mmol), 1-bromo-4-chlorobutane(5 mmol), and potassium carbonate (15 mmol) was refluxed in 100 ml ofacetone for 6 h. This solution was then concentrated in a rotaryevaporator and diluted with ethyl acetate. This mixture was then washedwith brine, and the resulting organic layer was dried and purified bycolumn chromatography. The product was dissolved in isopropanol (50 ml)and was added with 1-(2-methoxyphenyl)-piperazine (5 mmol), sodiumcarbonate (15 mmol), and potassium iodide (5 mmol) at 25° C. and thereaction mixture was refluxed for 12 h. This solution was thenconcentrated in a rotary evaporator and diluted with methylene chloride.This mixture was then washed with brine, and the resulting organic layerwas dried and purified by column chromatography. The product wasdissolved in THF and was added with imidazole (15 mmol),triphenylphosphine (15 mmol), and diisopropyl azodicarboxylate (15 mmol)dropwise at 0° C. and warmed to room temperature. After 2 h, the solventwas removed and the residue was washed with brine, and then purified bycolumn chromatography.

¹H-NMR (CDCl₃, 200 MHz) δ 7.3 (s, 1H), 7.0 (m, 10H), 4.1 (t, 2H), 4.0(t, 2H), 3.8 (s, 3H), 3.1 (m, 4H), 3.0 (m, 2H), 2.7 (m, 4H), 2.6 (t,2H), 1.8 (m, 4H)

Example 481-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 47 was followed using 1H-1,2,4-triazoleas a reactant, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.0 (s, 1H), 7.8 (s, 1H), 7.0 (m, 8H), 4.4 (t,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 491-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 47 was followed using 1H-1,2,3-triazoleas a reactant, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.7 (s, 2H), 7.0 (m, 8H), 4.6 (t, 2H), 4.0 (t,2H), 3.8 (s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 501-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 47 was followed using 1H-1,2,3-triazoleas a reactant, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (s, 1H), 7.3 (s, 1H), 7.0 (m, 8H), 4.6 (t,2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 511-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 47 was followed using 1H-tetrazole as areactant, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.5 (s, 1H), 7.0 (m, 8H), 4.9 (t, 2H), 4.0 (t,2H), 3.8 (s, 3H), 3.3 (t, 2H), 3.1 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H),1.8 (m, 4H)

Example 521-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine

The procedure given in Example 47 was followed using 1H-tetrazole as areactant, instead of imidazole, to give1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 8.2 (s, 1H), 7.0 (m, 8H), 4.7 (t, 2H), 4.0 (t,2H), 3.8 (s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

Example 531-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-1-yl)-ethyl]-phenoxy}-butyl)-piperazine

The procedure given in Example 47 was followed using 5-Methyl-tetrazoleas a reactant, instead of imidazole, to give1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-1-yl)-ethyl]-phenoxy}-butyl)-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2˜7.0 (m, 8H), 5.0 (t, 2H), 4.0 (t, 2H), 3.8(s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.3˜2.5 (m, 5H), 1.8 (m, 4H)

Example 541-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-2-yl)-ethyl]-phenoxy}-butyl)-piperazine

The procedure given in Example 47 was followed using 5-Methyl-tetrazoleas a reactant, instead of imidazole, to give1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-2-yl)-ethyl]-phenoxy}-butyl)-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.2˜7.0 (m, 8H), 5.2 (t, 2H), 4.0 (t, 2H), 3.8(s, 3H), 3.1 (m, 6H), 2.7 (m, 4H), 2.3˜2.5 (m, 5H), 1.8 (m, 4H)

Example 552-{4-[4-(4-[1,2,3]-triazol-1-ylmethyl-phenoxy)-butyl]-piperazin-1-yl}-benzonitrile

The procedure given in Example 1 was followed using1-(2-cyano-phenyl)-piperazine and 1H-1,2,3-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give2-{4-[4-(4-[1,2,3]-triazol-1-ylmethyl-phenoxy)-butyl]-piperazin-1-yl}-benzonitrile.

¹H-NMR (CDCl₃, 200 MHz) δ 7.9 (s, 1H), 7.8 (s, 1H), 7.2 (m, 2H), 6.9 (m,6H), 5.5 (s, 2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.8 (m, 4H), 2.6 (t, 2H),1.8 (m, 4H)

Example 561-(2-chloro-phenyl)-4-[4-(4-[1,2,3]-triazol-2-ylmethyl-phenoxy)-butyl]-piperazine

The procedure given in Example 1 was followed using1-(2-chloro-phenyl)-piperazine and 1H-1,2,3-triazole as reactants,instead of 1-(2-methoxyphenyl)-piperazine and imidazole, to give1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine.

¹H-NMR (CDCl₃, 200 MHz) δ 7.6 (s, 2H), 7.2 (m, 2H), 6.9 (m, 6H), 5.6 (s,2H), 4.0 (t, 2H), 3.2 (m, 4H), 2.7 (m, 4H), 2.5 (t, 2H), 1.8 (m, 4H)

The therapeutic use of the compounds of general structural formula (I)and their pharmaceutically useful salts are demonstrated by thefollowing tests.

Example 57 Serotonin 1A(5-HT1A) Receptor Inhibition Assay

The method to test the ability of compounds to inhibit serotonin1A(5-HT1A) receptors was using Hall. et al., J Neuro Chem., 1985, 44, p1685˜1696 with modification.

The Sprague-Dawley (SD) rats were killed by decapitation and theirbrains rapidly removed at 4° C. The cortex tissue were homogenized in 30volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.4) using an ultra-turraxT8 and centrifuged at 48,000 g for 20 min. The supernatant was discardedand the pellet washed twice by resuspension in 20 volumes Tris-HCl andcentrifugation, homogenized in 20 volumes Tris-HCl, and incubated at 37°C. for 10 min. Membranes were than collected by centrifugation andwashed twice before final resuspension in 10 volumes of 50 mM Tris-HCl,pH 7.4.

For binding assays, the incubation medium consisted of 162.5 ug oftissue homogenate, 0.92 nM of [3H]8-OH-DPAT and vehicle or 10 uM of 5-HTor 10 nM of test compounds per well. 5-HT and test compounds weredissolved in distilled water and incubation medium was 50 mM Tris (pH7.4 at room temperature). The assay plates (96 well) were incubated for60 min at 25° C. The reaction was terminated by rapid filtration using aTomtec harvester, through GF/C glassfibre filter with 5 times washes ofTris buffer. The radioactivity retained on the filters was counted byscintillation spectroscopy (MicroBeta TriLux, Wallac). The tests weretriplicates. Percent inhibition was calculated as below equation.

${\% \mspace{14mu} {inhibition}} = \frac{{{Total}\mspace{14mu} {binding}} - {{Compound}\mspace{14mu} {binding}}}{{{Specific}\left( {{Total} - {Nonspecific}} \right)}\mspace{14mu} {binding}}$

Total binding is the value of vehicle treated group and specific bindingis the values that deduct non-specific binding (i.e. the value ofnon-specific ligand, 5-HT).

The results obtained by testing compounds of the invention are given inthe following Table 1.

TABLE 1 Test Compound 5-HT1a % inhibition, at 10 nM Example 1 83.1Example 2 80.3 Example 3 77.8 Example 4 75.9 Example 5 50.7 Example 650.1 Example 7 78.4 Example 8 81.6 Example 9 52.2 Example 10 71.8Example 11 61.8 Example 12 60.9 Example 13 50.4 Example 14 51.1 Example15 23.5 Example 16 62.5 Example 17 56.4 Example 18 69.5 Example 19 59.6Example 20 68.5 Example 21 38.2 Example 22 53.4 Example 23 17.2 Example24 51.6 Example 25 45.2 Example 26 47.0 Example 27 40.9 Example 28 13.5Example 29 45.8 Example 30 38.3 Example 31 30.3 Example 33 53.7 Example35 73.3 Example 36 28.1 Example 37 24.8 Example 38 29.4 Example 39 52.9Example 40 45.6 Example 41 82.1 Example 42 36.2 Example 43 95.6 Example44 17.4 Example 45 73.8 Example 46 64.6 Example 47 70.0 Example 48 48.0Example 49 45.0 Example 50 51.0 Example 51 47.0 Example 52 62.0 Example53 46.0 Example 54 71.0 Example 56 24.3

Example 58 Tail Suspension Test in Mice (TST)

Tail Suspension Test in mice is the well-known animal model to determineantidepressant efficacy of compounds by checking escaping behavior andimmobility time of mice. Mice treated with antidepressant drug showescaping behavior continuously comparing with control group.

The mice were mainly treated orally with the test compound dissolved in30% PEG400 or with only 30% PEG400 as control. Tail of mouse issuspended to the rod of TST equipment and end of tail is fixed withsticky tape. Suspended mouse is incubated during 2 min for training andadaptation and after following 2 min, observe escaping behavior andcheck immobility time for 4 min. The potent ability of the compounds wasdetermined as percent value of reduction in immobility comparing tocontrol group as 100% baseline.

The results obtained by testing compounds of the invention are given inthe following Table 2:

TABLE 2 Test Compound % reduction at 1 mg/kg, po Example 5 21.2 Example7 21.1 Example 8 19.6 Example 11 25 Example 12 12.7 Example 18 14.7Example 19 50.6 Example 33 26.8 Example 39 30.4 Example 40 10.6 Example41 14.1 Example 48 26.2 Example 49 34.3 Example 50 46.9 Example 51 14.7Example 52 26.4 Example 54 31.8 Estalopram 47, at 30 mg/kg, po Fluxetine49. at 30 mg/kg, po

This anti-depressant effect, as with other anti-depressant drugs,suggested potentials for treating depression.

Example 59 Anti-Marble Burying Behavior Test in Mice

Marble burying was developed and validated as a pre-clinical assay ofpotential anxiolytic activity (Andrews and Broekkamp (1993). Proceduresto Identify Anxiolytic or Anxiogenic agents. In BehaviouralNeuroscience, ed. A Sahgal, pp. 37-54. IRL Press, Oxford). The marbleburying test places a naive mouse into a novel environment containing 25marbles (arranged on top of a sawdust surface). A reduction in thenumber of marbles buried by the mouse was hypothesized to be ananxiolytic-like effect.

The results obtained by testing compounds of the invention are given inthe following Table 3:

TABLE 3 Test Compound % reduction, at 3 mg/kg, ip Example 1 28.7 Example2 93.3 Example 5 60.3, at 7.5 mg/kg, ip Example 7 61.1, at 7.5 mg/kg, ipExample 11 69.0, at 7.5 mg/kg, ip Example 12 97.3 Example 19 50.8, at7.5 mg/kg, ip Example 20 27.0, at 7.5 mg/kg, ip Example 21 29.9 Example24 62.6 Example 28 24.6 Example 32 27.8, at 7.5 mg/kg, ip Example 3625.3 Example 47 39.3 Example 48 31.3 Example 50 96.8, at 7.5 mg/kg, ipExample 51 44.4, at 7.5 mg/kg, ip Buspirone  56.0, at 20 mg/kg, ip

An anti-marble burying effect, as with other anti-anxiety drugs,suggested potentials for treating anxiety.

Example 60 Prophetic

A compound according to this invention is used to treat depression. Aclinical dosage of 1 po (the basis of m-TST): 10 mg/human is used.

Example 61 Prophetic

A compound according to this invention is used to treat anxiety. Aclinical dosage of 3 ip (m-MB): 30 mg/human is used.

Example 62 Prophetic

A capsule for the treatment of depression is prepared by conventionalmethods and formulated as follows:

Excipients: Avicel 102 (microcrystalline cellulose).

Capsule size: size “0”

TABLE 4 Ingredient Amount Compound prepared in 10 mg Example 48Microcrystalline cellulose 240.7 mg Sodium starch glycolate 8 mgMagnesium stearate 1.3 mg Total amount (net fill weight 260 mgrequirement)

One or two capsules per day are administered to a human of 60 kg.

Example 63 Prophetic

A capsule for the treatment of anxiety is prepared by conventionalmethods and formulated as follows:

Excipients: Avicel 102 (microcrystalline cellulose).

Capsule size: size “0”

TABLE 5 Ingredient Amount Compound prepared in 30 mg Example 48Microcrystalline cellulose 220.7 mg Sodium starch glycolate 8 mgMagnesium stearate 1.3 mg Total amount (net fill weight 260 mgrequirement)

One or two capsules per day are administered to a human of 60 kg.

1. A piperazine compound represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein n is an integerfrom 2 to 6; R1 and R2 are the same or different and are independentlyselected from the group consisting of hydrogen, a hydroxyl group, ahalogen, nitrogen dioxide, a straight or branched chain alkyl group with1 to 4 carbon atoms, and a straight or branched chain alkoxy group with1 to 4 carbon atoms; R3 is a C1-C2 alkylene; and R4 is selected from thegroup consisting of: (a) a C2-C6 dialkylamine, (b) a 5 to 9-memberedaromatic amine wherein the ring is independently substituted with atleast one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclicalkyl, a C6-C10 aryl group and a halogen, (c) a 5 to 9-memberedheteroaromatic amine comprising at least a nitrogen atom as a ringconstituent wherein the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group and a halogen, (d) a 5 to 9-membered heterocyclic ringcomprising at least a nitrogen atom as a ring constituent wherein thering is independently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen, and (e) a 5 to 9-membered heteroaromatic ring comprising atleast a nitrogen atom as a ring constituent wherein the ring isindependently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen; and R4 is connected to R3 group through a nitrogen atomtherein.
 2. The piperazine compound of claim 1, wherein R4 isdimethylamine or diethylamine.
 3. The piperazine compound of claim 1,wherein R4 is connected to R3 through a nitrogen atom in an amino groupof the 5 to 9-membered aromatic amine or heteroaromatic amine.
 4. Thepiperazine compound of claim 3, wherein R4 is a 5 or 6-membered aromaticamine substituted with at least one of hydrogen, a C1-C6 alkyl, and ahalogen.
 5. The piperazine compound of claim 4, wherein R4 is a6-membered aromatic amine substituted with hydrogen.
 6. The piperazinecompound of claim 3, wherein R4 is a 5 or 6-membered heteroaromaticamine substituted with at least one of a C1-C6 alkyl and a halogen,wherein the heteroaromatic amine comprises at least two heteroatoms asring constituents where a first heteroatom is N and a second heteroatomis independently selected from the group consisting of N, O, and S. 7.The piperazine compound of claim 6, wherein R4 is a 5-memberedheteroaromatic amine having a structure (II) selected from the groupconsisting of:


8. The piperazine compound of claim 1, wherein R4 is connected to R3through a nitrogen atom contained in a ring as a heteroatom of the 5 to9-membered heterocyclic ring or heteroaromatic ring.
 9. The piperazinecompound of claim 8, wherein R4 is a 5 or 6-membered heterocyclic ringhaving a structure (III) selected from the group consisting of:


10. The piperazine compound of claim 8, wherein R4 is an azole selectedfrom the group consisting of diazole, triazole, tetraazol,benzotriazole, imidazole, pyrazole, benzimidazloe, and indazole.
 11. Thepiperazine compound of claim 10, wherein the azole has a structure (IV)selected from the group consisting of:


12. The piperazine compound of claim 1, wherein R1 and R2 areindependently selected from the group consisting of hydrogen, a halogen,a straight or branched chain alkyl group with 1 to 4 carbon atoms, and astraight or branched chain alkoxy group with 1 to 4 carbon atoms. 13.The piperazine compound of claim 1, wherein said compound is selectedfrom the group consisting of:1-[4-(4-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-[4-(3-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine-hydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazinehydrochloride,1-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzoimidazole,1-(2-Methoxy-phenyl)-4-{4-[4-(2-methyl-imidazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-indazole,1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzotriazole,1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-aminedi-hydrochloride,1-(2-methoxy-phenyl)-4-[4-(4-piperidin-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-phenyl-amine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-thiazol-2-yl-amine,1-(2-chloro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,4-(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,1-{4-[4-(4,5-dichloro-imidazol-1-ylmethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine,1-(2-chloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,4-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,(4-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,1-(3-fluoro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2,3-dichloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine,1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine,1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine,(4-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine,4-(4-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-morpholine,1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine,1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-[1,3,4]thiadiazol-2-yl-amine,1-(2,3-dichloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine,(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine,(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine,1-{4-[4-(2-imidazol-1-yl-ethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine,1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-1-yl)-ethyl]-phenoxy}-butyl)-piperazine,1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-2-yl)-ethyl]-phenoxy}-butyl)-piperazine,2-{4-[4-(4-[1,2,3]-triazol-1-ylmethyl-phenoxy)-butyl]-piperazin-1-yl}-benzonitrile,and1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine.14. A pharmaceutical composition comprising: (A) an effective amount ofa piperazine compound represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein n is an integerfrom 2 to 6; R1 and R2 are the same or different and are independentlyselected from the group consisting of hydrogen, a hydroxyl group, ahalogen, nitrogen dioxide, a straight or branched chain alkyl group with1 to 4 carbon atoms, and a straight or branched chain alkoxy group with1 to 4 carbon atoms; R3 is a C1-C2 alkylene; and R4 is selected from thegroup consisting of: (a) a C2-C6 dialkylamine, (b) a 5 to 9-memberedaromatic amine wherein the ring is independently substituted with atleast one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclicalkyl, a C6-C10 aryl group and a halogen, (c) a 5 to 9-memberedheteroaromatic amine comprising at least a nitrogen atom as a ringconstituent wherein the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group and a halogen, (d) a 5 to 9-membered heterocyclic ringcomprising at least a nitrogen atom as a ring constituent wherein thering is independently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen, and (e) a 5 to 9-membered heteroaromatic ring comprising atleast a nitrogen atom as a ring constituent wherein the ring isindependently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen; and R4 is connected to R3 group through a nitrogen atomtherein; and (B) a pharmaceutically acceptable carrier or excipient. 15.A method for treating at least one of depression and anxiety in a mammalcomprising administering to a mammal in need thereof an effective amountof a piperazine compound represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein n is an integerfrom 2 to 6; R1 and R2 are the same or different and are independentlyselected from the group consisting of hydrogen, a hydroxyl group, ahalogen, nitrogen dioxide, a straight or branched chain alkyl group with1 to 4 carbon atoms, and a straight or branched chain alkoxy group with1 to 4 carbon atoms; R3 is a C1-C2 alkylene; and R4 is selected from thegroup consisting of: (a) a C2-C6 dialkylamine, (b) a 5 to 9-memberedaromatic amine wherein the ring is independently substituted with atleast one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclicalkyl, a C6-C10 aryl group and a halogen, (c) a 5 to 9-memberedheteroaromatic amine comprising at least a nitrogen atom as a ringconstituent wherein the ring is independently substituted with at leastone of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, aC6-C10 aryl group and a halogen, (d) a 5 to 9-membered heterocyclic ringcomprising at least a nitrogen atom as a ring constituent wherein thering is independently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen, and (e) a 5 to 9-membered heteroaromatic ring comprising atleast a nitrogen atom as a ring constituent wherein the ring isindependently substituted with at least one of hydrogen, a C1-C6aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and ahalogen; and R4 is connected to R3 group through a nitrogen atomtherein.
 16. The method of claim 15, wherein the piperazine compoundrepresented by Formula (I) is administered in a pharmaceuticalcomposition, wherein the pharmaceutical composition further comprises apharmaceutically acceptable carrier or excipient.